Skin cancer is the most common form of cancer in humans, and in some countries it accounts for about half of all tumors. Among all tumors of humans, basal cell carcinoma (BCC) is the most common cancer of white populations, and constitutes the 80% of the cases of skin cancer. BCC is a slowly-growing, locally invasive malignant epidermal skin tumor; it tends to infiltrate and destroy contiguous tissues, but metastatic diffusion is extremely rare. In the initial forms a superficial translucent nodule, waxen or grey-pearly color, or a pink or red spot with scarce abnormal blood vases, are often present. The most advanced forms show ulceration, particularly in central zone, and peripheral borders, in relief. It can appear in every part of the body, but 90% of the lesions appear in the face and on the head. BBC most frequently occurs in light-skinned, middle aged to old patients, with a history of ultraviolet exposure, but may also arise in basal cell nevus (Gorlin's syndrome). Australia has the highest rate of BCC in the world, and certain regions have an incidence of up 2% per year. Once a person has developed a BCC, there is a significantly increased risk of developing subsequent BCC's at other sites. Evidence suggests that BCC may arise from the multi-potent cells in the basal layer or follicles of the skin. There are several different histological and pathological clinical forms of BCC, but traditional diagnostic methods do not provide enough information on tumor features.
Squamous cell carcinoma (SCC) is an epithelial malignancy with morphologic features of squamous cell differentiation, without additional features suggestive of other differentiated tissues. It can appear in every part of the body, and can also develop on lips, vulva and penis; often it originates from burn scars or skin ulcers, and appears as a superficial lesion, that easily bleeds. Sometimes an ulceration develops, with thick crater-like borders; in other cases the lesion is covered by an horny layer. Other variants of skin cancers that originate from the cells of the superficial layer are represented by a particular SCC in-situ, called Bowen's disease, and by the “erythroplasia of Queyrat”, a superficial form of in-situ SCC of male genitals. A particular form of SCC is the keratoacanthorma, in which a bulge or thick mass, often ulcerated, is formed in the parts of the body exposed to the sun. Finally, also the common actinic keratosis is today considered, in dermatology, an initial form of carcinoma in-situ. SCC is the second most common form of skin cancer, with over 200,000 new cases per year reported in the United States. The highest incidence occurs in Australia, where the age-adjusted incidence has been calculated to be 1332 cases per 100,000 population for men, and 755 cases per 100,000 population for women. In European countries, the annual rate of incidence of SCC is actually of about 25 cases per 100,000 people. SCC of the skin may metastasize to regional lymph nodes and is often locally recurrent.
The incidence of both BCC and. SCC increases with age, begins after the age of 30 years, peaks at the age of 65-70 years, and occurs more often in men than in women. Both tumors appear most frequently on the face, neck, bald scalp, hands, shoulders, arms and back; the rim of the ear and the lower lip are especially vulnerable to these cancers. The clinical appearances and morphology of both tumors are diverse, including nodular, cystic, ulcerated (‘rodent ulcer’), superficial, morphoeic (sclerosing), keratotic and pigmented variants. Ulceration is especially common in large tumors, in long-standing or aggressive lesions. The risk factors include sun exposure, exposure to ionizing radiation, arsenic exposure, coal tar derivates and ultraviolet A radiation exposure. It is also recognized the importance of commonly predisponent factors, like immunosuppression, and physical characteristics, as fair complexion, red or blond hair, and light eye color.
BCC is characterized by a non-aggressive behavior, given its low metastatic potential (0.03 to 0.6%), but metastases have been described in the subcutaneous tissue, bones, lungs, liver, lymph nodes of the neck. SCC has a more aggressive behavior, and metastatic potential is higher (2% to 5%), but in some forms (like invasive Bowen, desmoplastic SCC, malignant proliferating pilar tumor/cyst, de-novo SCC, adenosquamous cell carcinoma, SCC arising from radiation, burn scars, cronic conditions or immunosuppresion) this risk raises to 10% and more.
The data furnished by the patient, and the objective examination of the lesions by an experienced dermatologist is of fundamental importance for a correct diagnosis. Nevertheless, only the microscopic (histology/cytology) examination can furnish the exact characterization and classification. The collecting of the tissue can be performed by surgical excision or by /biopsy through a special metallic punch (biopsy punch); sometimes a simple cytological examination of the scarified lesion is sufficient to confirm the diagnosis. The dermoscopic epiluminescence, largely employed for the diagnosis of pigmented lesions, allows the observation of characteristics features and of the vascular network to the lesion; the observation of the neoangiogenesis that characterizes the cancer lesion usually furnishes useful elements of judgment on the extension and depth of the lesion. For SCC, due to the high risk of metastatic diffusion, an accurate periodical examination of the patients is mandatory.
Clinical exams include a full body skin examination, palpation of previous excision sites and examination of the skin between primary tumor sites and draining lymph nodes for in-transit metastasis. Regional lymph nodes should be palpated for lymphadenopathy and any suspicious lymph node enlargement should be evaluated by biopsy, imaging, or both. Imaging techniques using CT or CT/PET are useful for staging and detecting distant disease. MRI provides superior resolution of soft tissue tumors, particularly in the head and neck region and should be considered for metastases that occur in these regions. Sentinel lymph node localisation and lymphoscintigraphy by 99mTc colloid should be included, before and after therapy, of all suspect cases. Characteristics or primary tumors that develop into metastatic SCC include area >120 mm2, invasion to a depth >3.2 mm, and invasion of underlying fat, muscle or bone.
The surgery practice is widespread performed, with margins of 2-4 mm recommended for nodular, well delineated, tumors sized up to 2 cm; for those larger than 2 cm, excision with margin of 1 cm, or more, is usually suggested, especially for tumors with aggressive course. Mobs' technique offers the best chances for cure and maximally preserves healthy tissue; it consists in the progressive histological real-time examination of tissue sections of the lesion during the surgery, up to the reaching of the healthy tissue.
In all cases in which tumors are located in areas on which surgery excision may be very difficult (ear, nose, eyelids), the aesthetic and functional results are often highly unsatisfactory. When the lesion is rather large, and the residual healthy skin is not sufficient for a satisfactory surgical suture, it is necessary to proceed to a plastics reconstructive surgery, with transplantation of healthy skin (usually from the inferior limb or from the gluteus skin). The cosmetic outcome is often unsatisfactory; if a relapse raises in transplanted skin, the management of the lesions becomes highly problematic. For both tumors, standard therapies like curettage and electrodessication, surgery, cryosurgery, and intralesional interferon therapy are often proposed to the patients. New alternative topical therapy are now available for the treatment of selected cases, such as tumors located in critical, or inoperable patients, owing to systemic underlying diseases (cardiomyopathy, pulmonary insufficiency). They include imiquimod, an immune response modifier used for the treatment of superficial BCC less than 2 cm in diameter, tazarotene, a retinoic acid, generally used for topical treatment of psoriasis, and proposed for the local treatment of BCC, photodynamic therapy, which involves the administration of a tumor-localizing photosensitizing agent and its subsequent activation with visible light to cause selective destruction of the tumor. The use of imiquimod cream was an effective treatment option for superficial and nodular basal cell carcinomas, giving a clearance rate of 89.5% at an average of 39 months of follow up (Vun Y, Siller G, Australas J Dermatol. 2006 August; 47(3):169-71). The use of photodynamic therapy with porfimer sodium at 1 mg/kg produced, at 5-year, recurrence rates of 28% and 15% for sporadic and nevoid basal cell carcinoma syndrome (NBCCS) lesions, respectively (Oseroff A R, Blumenson L R, Wilson B D, Mang T S, Bellnier D A, Parsons J C, Frawley N, Cooper M, Zeitouni N, Dougherty T J, 2006 June; 38(5):417-26). By the use of meso-tetra-hydroxyphenyl-chlorine (m-THPC) mediated photodynamic therapy, good cosmetical results, with little or no scarring, were obtained in 87% of the treated lesions (Triesscheijn M, Ruevekamp M, Antonini N, Neering H, Stewart F A, Baas P, Photochem Photobiol 2006 Jul. 1).
All these treatments are used for small, superficial and not recurrent BCC, but are not indicated for nodular, cystic, infiltrative and morphoeic variants. Irradiation by photons has been used to deliver doses ranging from 20 to 73 Gy, in single or multiple treatments of BCC. The 5-year local control rate for recurrent Stage I and II carcinomas was 95%. (Wilder R B, Kittelson J M, Shimm D S., Cancer 1991; 68:2134-37). These results suggested that high cure rates can be obtained in basal cell carcinomas treated with radiation therapy, with cure rates comparable to Mohs micrographic surgery, which in these tumors is generally considered the “golden standard” treatment. Irradiation by conventional methods (radiotherapy by external beam X-rays or gamma rays), due to the penetrating nature of the photons, however, cannot be recommended for treatment of tumors in areas in which radiation can be very harmful (face, eyes), and has proven itself unsatisfactory in the treatment of SCC. The interstitial brachytherapy with needles or seeds of 192Ir has been employed in cases of SCC of the penis (T1, T2 and T3, and also in the carcinoma in-situ). The results significantly change with tumor grade; the preservation of the penis after 5 years has been 86% of all treated cases.
Radioactive sources in thin layer as used in e.g. brachytherapy are usually obtained by electrolytic deposition of a radioactive element on a metallic substrate. In such sources, the distribution of the radioactivity on the substrate material must be uniform, in order to impart a homogeneous dose rate from the surface of the source. The sources are generally used in the calibration of instruments for the measurement of the radioactivity of surfaces, but can also be used in the radiotherapy of superficial tumors. In the past, radioactive sources, in the form of metallic plaques containing the emitters 106Ru or 90Sr, have been used in the brachytherapy of ocular melanoma (Anteby et al., Ann Ophtamol, 1993, 25(9):339-41).
WO 2005/079757 discloses a method in which a radioisotope is mixed and/or reacted with a thermogelling biodegradable polymer, obtaining a product that can be applied directly inside a body tissue. to a tumor site, after surgical excision of the tumor mass, to destroy vestigial cancerous cells. The polymer should be injected into the body, and the obtained material must in all respect be classified as a radiopharmaceutical product. Consequently the attention of the inventors is strictly directed to the obtainment of a biodegradable, non-toxic, chelating polymer for intra-corporeal injective application, consisting in various combinations of fibrin, polypeptides, polyethylene-glycol blocks, biodegradable polyester blocks, as explicitly disclosed in the appended claims of WO 2005/079757. In the description or claims, however, brachytherapy treatment of skin tumors is not mentioned.
In U.S. Pat. No. 7,192,395 a method is disclosed in which a polymer is used as carrier of radioisotope in the preparation of radioactive balloons or wires. The document describes the coating of different material with polymers that have the ability to chelate different radioactive ions, and is aimed to obtain radioactive balloons for medical use, to be used in brachytherapy post-transluminal coronary angioplasty. While in the description of U.S. Pat. No. 7,192,395 a series of experiments on the chelation of ions on polymers, and an exposition of the general methods for the coating of plastic material by radioactive isotope ions are reported, the treatment of skin tumors is not mentioned, the attention being rather directed to the obtainment of non-toxic, chelating films, with low leaching of free radioisotope ions, to be used in the blood stream. Consequently, U.S. Pat. No. 7,192,395 is exclusively aimed to the intra-corporeal application of post-transluminal angioplasty brachytherapy, as clearly disclosed in the appended claims of the document.
In WO 99/42177 a radioactive stent is described, aimed to prevent restenosis by performing a brachytherapy after the endoluminal insertion of said stent apparatus. In order to render the stent radioactive, a layer of radioactive ions is deposited on the surface of the metallic stent. While a general description of the possible materials and methods for covering a metallic item with a radioactive polymer is presented in WO 99/42177, the treatment of skin tumors is not mentioned. The attention of this document is essentially focused and directed to the obtainment of a biocompatible cover radioactive polymer for a fixed metallic item (stent), to be used in an intra-corporeal application of post-transluminal angioplasty brachytherapy, as clearly disclosed in the appended claims of the document.
In U.S. Pat. No. 6,394,945 a radioactively coated substrate, and some methods for producing radioactive coatings on such substrates, are described. More specifically, this invention embraces the coating of implantable medical devices such as stents, catheters, radioactive seeds and the like for use in medical treatments with radioactive isotopes. While the invention relates to a method of producing a uniform permanent, distribution of radioisotope on a surface of a medical device, by using electroplating, the treatment of skin tumors by direct application on the patient is not mentioned, the attention being rather directed to the obtainment of medical device covered with radioisotopes, as clearly disclosed in the appended claims of the document.
In US 2007/265485 a device and method for localized delivery of beta radiation in surgical procedures, particularly ophthalmic procedures, is described, in which a localized delivery of beta radiation to treat Age Related Macular Degeneration is performed. The proposed device delivers beta radiation to the affected sub-macular region, and the device includes a radiotherapy emitting material positioned on the distal end or portion of the device, such as a shielded bent cannula. Also in this case in the description or claims of US 2007/265485, the brachytherapy treatment of skin tumors is not mentioned. The attention of the description is exclusively directed to the obtainment of a shielded, fixed, medical device, containing a radioactive isotope, to be used as a classical brachytherapy apparatus in ocular pathologies, as clearly disclosed in the appended claims of the document.
In US 2007/053830 a method of manufacture, treatment and compositions for an implant which permits localized delivery of labelling agents for therapy and diagnosis is disclosed. The labelling agent is a radioactive isotope for radiotherapy, incorporated into bioresorbable particulates with minimal leakage of the radioisotope. Therefore, one aspect of the application provides a biocompatible implant material which is resorbable, yet retains its chemical and physical integrity for a desired length of time, while a radioisotope or combination of radioisotopes is retained at a desired site, e.g. localized when implanted into the body of a patient. A particular embodiment relates to a radioactive resorbable implant material for localized radiotherapy, or radioembolization containing a resorbable base glass matrix in form of microspheres or fibers, with surface being of great chemical durability in human body fluids. The resorbable materials are used for localized radiotherapy through injection or surgical procedures. The material has to be injected into the body; consequently the attention of the inventors is strictly directed to the obtainment of a non-toxic material for intra-corporeal infective application, as explicitly disclosed in the appended claims of the document. In the description or claims of US 2007/053830, the brachytherapy treatment of skin tumors is not mentioned, and, consequently, no attention is focused on the medical methods and procedures for a selective irradiation of skin tumors.
In the case of skin tumors, the radiotherapy shows the premises for excellent cure rates, but drawbacks of external beam classical radiotherapy techniques strongly lower the clinical effectiveness; in such tumors an external irradiation selectively imparting a localized dose only to the cancer lesions, by sparing the healthy tissue, i.e. a topical administration of a radiation therapeutic dose, only directed to the skin tumor lesions, should be highly desirable. Therefore, an object of the present invention is to provide an improved radiotherapy method for treating skin tumors.